Abstract Severe mental illness and substance use disorder frequently co-occur. Individuals suffering from schizophrenia?a common, persistent, and severe mental illness?have much higher rates of heavy alcohol use and smoking than the general population. Similarly, individuals with substance use disorder often suffer from other mental illnesses. For example, 22% of individuals with alcohol use disorder have another mental illness, compared to 11% of individuals without alcohol use disorder. Despite the prevalence of comorbidity, it is not known whether shared genetic factors contribute to schizophrenia and substance use disorders. In this study, we use existing genome-wide association study (GWAS) data and state-of-the-art statistical methodology to evaluate whether schizophrenia shares genetic factors with alcohol use disorder or nicotine dependence. Specifically, in aim 1 we will evaluate whether genetic factors that contribute to schizophrenia also contribute to alcohol use disorder and to nicotine dependence. Then, in aim 2, we will evaluate whether genetic factors that contribute to either alcohol use disorder or nicotine dependence also contribute to schizophrenia. This novel proposal is significant because it will lead to improved understanding of comorbidity of schizophrenia with alcohol use disorder and with nicotine dependence at a genetic level.